Nora Fritz, PhD, PT, DPT, NCS · 2018. 4. 2. · Nora Fritz, PhD, PT, DPT, NCS CMSC Annual Meeting 5.29 ... • Rhul Marasigan • Allen Jiang National MS Society Research Grant ...

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Evaluating Cerebellar Contributions to Physical Performance and Cognition in Multiple Sclerosis

Nora Fritz, PhD, PT, DPT, NCSCMSC Annual Meeting

5.29.15

Background

• Individuals with multiple sclerosis (MS):– 85% report gait (motor) dysfunction that interferes with daily functioning (Kelleher et al. 2010)

– 40‐65% report cognitive dysfunction (Amato et al. 2010)

• The cerebellum:– Plays an important role in both motor and cognitive processing (Koziol et al. 2014; Stoodley et al. 2012)

– Is a common site for MS‐related disability (Weier et al. 2015)

• Cerebellar signs and symptoms are the predominant manifestation in 11‐33% of individuals with MS (Weier et al. 2015)

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Structure‐Function Relationships

• Rehabilitation for individuals with cerebellar dysfunction is limited– A better understanding of the relationship of clinical features to structural anatomy would be useful in this heterogeneous patient population.

• Ultimately:– Drive clinical practice forward

• Utilize what we know about these relationships to predict future function

• Develop more effective rehabilitation protocols that target mechanism of dysfunction/disability

Structure Function

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Cerebellar Anatomy

Inferior Cerebellar Peduncle (ICP)Middle Cerebellar Peduncle (MCP)Superior Cerebellar Peduncle (SCP)

Mori S, Zhang J. 2006

Background

• Diffusion:

– Primary outcome measures:

• Fractional Anisotropy (FA): degree of anisotropy in a given voxel

• Mean Diffusivity (MD): total diffusion within a voxel

Alexander et al. 2007

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Background

• Diffusion

– SCP FA Linked with rate of learning a visuomotortask in healthy adults (Della‐Maggiore et al. 2009)

SCP FA

Upper Limb Function(PPMS)

(Anderson et al. 2011)

MCP FA

T25FW Performance

(PPMS)(Anderson et al. 2011)

Balance Performance (RRMS, SPMS)

(Prosperini et al. 2013)

SCP MD

In PPMS vs. RRMS & Controls(Anderson et al. 2011)

Background

• Volumes

– Reduction in total cerebellar volume in MS compared to controls; more prominent in PPMS (Anderson et al. 2009; Calabrese et al. 2010)

– Established Relationships Between:

• Cerebellar lesion volume and cognition (Damasceno et al. 2014)

• Cerebellar grey matter volume and fine motor skill (Anderson et al. 2009)

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Objective

To examine the relationship of

motor and cognitive performance

to

cerebellar volumes and diffusivity measures

in individuals with MS.

Physical Function Measures

• Strength

• Sensation

Vibratron Physiotemp, Huron NJHand Held Dynamometer; Hoggan Health Industries, W Jordan UT

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Physical Function Measures

• Walking

• Timed Up and Go (TUG)

• Timed 25 Foot Walk (T25FW)

• Two Minute Walk Test (2MWT)

• Fast Walking Velocity

• Fall History

Cognitive Measures

• Symbol Digit Modality Test (SDMT)

(Parmenter et al. 2007; Deloire et al. 2006; Genova et al. 2009; Strauss et al. 2006; Drake et al. 2010; Rao 2004.)

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Structural Measures

• Philips 3T Scanner

• DWI for FA & MD measurement

• Automatic segmentation method (Ye et al., 2015)

Structural Measures• MPRAGE for volume measurement

• Automatic Segmentation with lobule parcellation(Yang et al. 2013; Bogovic et al. 2013)

• Lobules I‐V, VIII: related to motor function

• Lobules VI‐VII: related to cognitive function (Stoodley & Schmahmann, 2010)

(Schmahmann, 2000; Jung et al., 2012)

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Inclusion Criteria & Demographics• Diagnosis of Relapsing Remitting MS• No active exacerbations• No corticosteroid use in past 30 days• No other orthopedic or neurologic disorders that would

influence walking• Able to follow study‐related commands

AgeMean (SD)

Gender Symptom Duration Mean (SD)

EDSS Median (range)

MSn=29

50.0 ± 11.3 Years

18F; 11M 12.8 ± 9.9 years

4.0 [1‐6.5]

Control n=23

51.9 ± 11.0 Years

15F; 8M ‐‐ ‐‐

All values listed mean±SD with the exception of EDSS, which is listed median[range]

Comparisons between Individuals with MS and Controls

MSMean (SD)

ControlMean (SD)

P‐value

Falls(>1 past month)

0.52 (0.51) 0 (0) 0.0001

Summed Strength (lbs)

235.4 (89.6) 305.1 (64.4) 0.0029

Vibration Sensation (vu)

6.7 (3.5) 3.1 (2.3) 0.0001

Walk Velocity (m/s) 1.6 (0.49) 2.0 (0.35) 0.0077

TUG (s) 7.7 (2.3) 5.9 (1.1) 0.0021

T25FW (s) 5.6 (2.3) 4.2 (0.73) 0.0139

2MWT (m) 163.8 (45.4) 197.0 (32.4) 0.0057

SDMT 47.7 (12.4) 59.9 (6.2) 0.0001

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Diffusion Results

• Diffusivity of the SCP, was significantly worse in individuals with RRMS compared to controls.

– FA: p=0.029

0.45

0.46

0.47

0.48

0.49

0.5

0.51

Multiple Sclerosis Control

*

better

Diffusion Results

• Diffusivity of the SCP, was significantly worse in individuals with RRMS compared to controls.

– MD: p=0.002

0.00088

0.00092

0.00096

0.001

0.00104

0.00108

Multiple Sclerosis Control

*

better

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Diffusion Results

• Decreased MD in the SCP was significantly associated with:

– Reduced falls in the past month

• r=‐0.37; p=0.007

– Better SDMT performance

• r=‐0.45; p=0.0009

Diffusion Results

– Better performance on walking tests

• T25FW: r=0.29; p=0.044

• TUG: r=0.33; p=0.025

• 2MWT: r=‐0.39; p=0.009

• Walking speed: r=‐0.28; p=0.041

• Decreased MD in the SCP was significantly associated with:

r= ‐0.35r= 0.08

faster

better

SCP M

ean Diffusivity

Walk Velocity (m/s)

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Volume Results

• Higher volume of the motor lobules (I‐V, VIII) was significantly associated with:

– Higher strength

• r=‐0.37; p=0.007

– Better performance on the T25FW

• r=‐0.30; p=0.035

Volume Results

• Higher volume of the motor lobules (I‐V, VIII) was significantly associated with:

– Faster walking speed

• r=0.30; p=0.032

Volume of Lobules I‐V and VIII (mm

3)better

Walk Velocity (m/s) better

r= 0.33r= 0.22

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Volume Results

• Motor lobule volume was not related to sensory performance (r=0.23; p=0.108).

Volume Results• Higher volume of the cognitive lobules (VI‐VII) was associated with:

– Better performance on the SDMT

• r=0.43; p=0.002

Symbol Digit Modality Test (SDMT)

better

better

Volume of Lobules VI‐VII (mm

3)

r= 0.49r= 0.32

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Volume Results• Larger MCP Volume is related to:

– Better SDMT performance

• r=0.3703; p=0.0075

Symbol Digit Modality Test (SDMT)

better

better

Volume of Lobules VI‐VII (mm

3)

r= 0.39 r= 0.38

Volume Results

• Fallers (n=15) vs. non‐fallers (n=14)

• Fallers perform significantly worse on:

– Walk velocity (p=0.026)

– SDMT (p=0.010)

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Volume Results

• Fallers have lower volumes in:

– MCP (p=0.033)

– Lobules I‐V and VIII (p=0.038)

– Lobules VI‐VII (p=0.008)

better *

45000

50000

55000

60000

65000

70000

75000

80000

Fallers Non‐Fallers

better

10000

15000

20000

25000

30000

35000

40000

Fallers Non‐Fallers

*

better

90009500100001050011000115001200012500130001350014000

Fallers Non‐Fallers

*

Summary

• Cerebellar volumes and diffusivity are selectively associated with:– Physical performance

– Cognition

• Unique Findings in RRMS:– Differences in diffusivity among RRMS & controls.

– Differences among fallers and non‐fallers.

– Relationships among clinical impairment and diffusivity measures.

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Conclusion• Cerebellar MRI:

– Improves our understanding of:

• Structure‐function relationships in individuals with MS

• Individualized differences in this heterogeneous group

– May provide an avenue for:

• Understanding motor skill learning in MS

• Targeted, individualized rehabilitation

Structure Function

REHAB

Acknowledgments

Kennedy Krieger Kirby Center for Functional

Imaging• Kathie Kahl• Terri Brawner

Department of Neurology, Johns Hopkins School of

Medicine• Peter Calabresi, MD• Scott Newsome, DO• Pavan Bhargava, MD

Department of Biostatistics, Johns Hopkins School of

Public Health• Ani Eloyan, PhD

Kennedy Krieger Motion Analysis Lab

• Kathleen Zackowski, PhD, OTR

• Jennifer Keller, MS, PT• Chen Chun Chiang• Rhul Marasigan• Allen Jiang

National MS Society Research Grant

Department of Electrical & Computer Engineering, Johns Hopkins University

• Jerry Prince, PhD• Chuyang Ye, PhD• Zhen Yang

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